In the previous funding cycle we have demonstrated that syndecan 4, a transmembrane heparan sulfate carrying core protein, plays two important signaling roles in endothelial cells: regulation of Akt activity via control of mTOR complex 2 (mTORC2) assembly, and regulation of Rac1 activation. Both Akt and Rac1 are key regulators of cell migration, proliferation and survival. In addition, Akt is involved in regulation of angiogenesis while Rac plays an important role in shear stress response and regulation of vascular permeability. The unexpected involvement of syndecan 4 signaling in regulation of both of theses processes places it squarely in the center of two major signaling networks and suggests an important role for this gene in key biological processes. In studies outlined in this application we propose to explore in depth the role of syndecan 4 in regulation of these signaling pathways establishing both the molecular basis of syndecan 4 activity and functional consequences of disruption of its expression including effects on normal and pathological angiogenesis, arteriogenesis, and vascular permeability. Specifically, we propose the following three Aims: 1) molecular basis of syndecan 4 dependent regulation of mTOR activity;2) Functional significance of syndecan 4 dependent regulation of mTOR activity and 3) Syndecan 4 dependent regulation of Rac1 activation. Taken together, these three Specific Aims will provide a comprehensive insight into the syndecan 4 role in regulation of endothelial biology and produce novel insights into control of mTOR/Akt and Rac activities. PUBLIC HEALTH RELEVANCE "Vascular health" is an important medical issue relevant to a large spectrum of cardiovascular illnesses. This projects examines a functional role of a key molecule, syndecan-4, that regulates two key aspects of vascular biology;production of nitric oxide and cell replication and migration. A better understanding of syndecan-4 biology will directly contribute to therapeutic attempts at improving vascular health and developing treatments for cardiovascular diseases.